Saturday, 22 September 2012

Time to DEFINE and CONFIRM a new treatment for MS: BG12 is coming

Gold et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-107.

BACKGROUND: BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis.

METHODS: We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.


RESULTS: The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.


CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).




Fox et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012; 367(12): 1087-97

BACKGROUND: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).

METHODS: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.

RESULTS: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.

CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).

So BG12 a pill taken at least two times a day joins the other new agents Tysabri, Gilenya, Alemtuzumab, Movecto that has passed phase III and have moved the inhibition of relapse from rate from about 30% with the interferons, glaterimer acetate and the new Aubagio up to 50%. The most frequent side effects were a temporary flushing and warm feeling and gastrointestinal symptoms including nausea, diarrhea, cramping and vomiting. Though both types of side effects were common, they tended to diminish after the first few weeks of use and were tolerated by most patients. The regulatory submission for BG12 has already been made.

The next data we will see is the MRI data as the mechanism, which we sort of know because of the phase II study of action of BG12 suggests that it could have a neuroprotective action, in addition to the immunosuppressive/immunomodulatory action as shown by inhibition of relapse.

Whilst this is more good news for RRMSers, I think we will see Panaclar as BG-12 is going to be called, tried in PPMSers where it could be interesting because BG12 can help save nerves based on a mechanism of action. That is, if enough of it reaches the brain

Research: BG12 targeting Nrf2 to help save nerves
25 Jan 2012

Therefore this drug may have added or different benefits to the current stable of MS drugs.

As you know post G has made posts of the phase 3 study already...you get it here earlybut now is you chance to read it. BG12 is based on a psoriasis drug that has been around for years and the side effect profile looks reasonable.


CoI: None, 
        but Prof G in an author and is on the Clinical Trial Steering     Committee

32 comments:

  1. Thank you MouseDoc for bringing the topic up so soon after my original thread.

    However, I still don't know whether taking the drug with food diminishes the protective effect?

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  2. Brilliant news, and let's hope it helps with progressive, too.

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  3. Is BG12 immuno-suppressive? How great is the risl of excessive immuno-suppression (eg PML etc?) from taking this having already been treated with Alemtuzumab? My current plan is to take it as soon as licensed as a neuroprotective adjunct to the immunomodulatory Campath I've already had. I know there's no trial of this bit we have to make decisions in the here and now and, on balance, this seems to have an intuitive appeal as a treatment combo.

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    1. It is stopping relapses, if they are driven by the immune system then it is immunosuppressive in some way and as to lymphocyte depleting effects this has been occasionally noted in some studies. What this drug would do in an immune depleted individual is unknown. Maybe Prof G will comment here

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    2. Prof G? Would you risk BG12 after Alemtuzumab? Or perhaps a different oral possibly neuroprotective therapy? Off-label Amiloride (apparently Alisdair Coles preferred candidate for neuroprotection according to an article in Multiple Sclerosis Journal) or laquinimod? I'm committed to add something to my efforts so I can feel I've done all I can based on the state of present knowledge and so just need some help selecting from different possible candidates... Please?!

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    3. I can't recommend anything without the evidence (clinical trials). However, the strategy of combining an anti-inflammatory with a neuroprotective agent is what most of us have been talking about for a decade or more. The problem is we have not had a neuroprotective drug to use in this way.

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    4. I understand your position. Perhaps you can answer these though?

      1. Do you think there are likely to be safety issues from BG12 if used in this way?

      2. Do you believe BG12 - or laquinimod or Amiloride - are directly neuroprotective (as opposed to indirectly via anti-inflammatory properties)?

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  4. The protocol of the DEFINE study states that:
    "New or recurrent neurologic symptoms that occur less than 30 days following the onset of a protocol-defined relapse should be considered part of the same relapse".

    How many of these not-counted-relapses were in each of the three groups of patients? Their number is as important as the counted-relapses, since no one really knows if they correspond to exactly the same CNS damage.

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  5. How many of these.....

    One has no idea as the data comes from a large number of different sites and is collated by the company leading the trial......Are you insinuating this is a case of "Bad Pharma" or a publicity question as Ben Goldacre has a new book new week called bad Pharma (http://www.guardian.co.uk/business/2012/sep/21/drugs-industry-scandal-ben-goldacre?INTCMP=SRCH) so you can get your conspiracy theroies going.

    However you have a protocol in trials to define relapses and this is how it is reported but surely the chance is equal in all groups.

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    1. Have I just read this response correctly?
      This chap raised a legitimate observation that obviously doesn't sit well with your camp and you immediately try and belittle that question.
      Your response has prompted me to research a little more.
      My feelings on the subject at this point?
      Me thinks the 'mousedoctor' doth protest too much.
      Many thanks Mr.Vasilopoulos.

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  6. The point is that "relapse" is such a vague and stretchable term that can not handle the weight of the conclusions based on it. The fact that there was a special committee to tell protocol-defined-relapses from mere episodes reveals the weakness and fallacy of using "relapses" as primary treatment goals.

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    1. reveals the weakness and fallacy of using "relapses" as primary treatment goals.

      We are well of your view that relapses are of no consequence to MS, we can agree to disagree and am happy for you to keep your head in the sand.

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    2. Listen to Prog G's talk: he pushes the idea of using something more standardised instead of relapses & EDSS

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    3. "relapses are of no consequence to MS"
      Relapses are the clinical manifestation of the immune REACTION to the CNS damage. By choosing to reduce relapses through disabling the immune system you only succeed in reducing the SIGNS of damage, not the AMOUNT of damage. You may come to accept this one day.

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    4. So why do people who have relapses that leave them with disability that was not there before the relapse suddenly get extra disabily?.

      With your argument the disability will still occur without the relapse. We are not talking creeping progression but step wise

      This would have been obvious in the Gilenya trials, the tysabri trials, cladribine trials, alemtuzumab trials involving thousands of MSers maybe other Bloggers can offer their experience

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    5. "With your argument the disability will still occur without the relapse."

      This is exactly the case with progressive forms of MS, isn't it?. The number of relapses does not depend only on the number and severity of the CNS damage, but also on the strength of the immune system to respond. Seen that way, more relapses don't necessary mean more severe MS, but a better, healthier immune system. By using immunomodulatory drugs you weaken the response to the damage. Some immune systems resist (the healthier) and get tagged "not responders".

      "So why do people who have relapses that leave them with disability that was not there before the relapse suddenly get extra disabily?."

      So, your question is how is progression possible without relapses and why relapses tend to cease as disability progresses. The answer is in the different way that damage occurs in the brain and the spinal cord. Damage in the brain occurs "step wise" as you say. There is no preparation for the the next episode (at least in the early stages of MS). On the contrary, the spinal cord suffers constant, slight afflictions that weakens it as whole, becoming more and more fragile. So the SP type of MS is the passage from active life with relapses to restricted life with progression. The reduction in activity shifts the burden to the spine. I don't know if the immune system can somewhat adapt and reduce its (futile) response to the constant damage. This could be a complementary explanation.

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  7. Question to Anonymous who is using fumarate:
    Are you getting BG12 as part of a trial? Or is it the psoriasis drug - in which case do you import it or are you in Germany?

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  8. No, I'm getting fumarate/ not BG12(in Germany) from a doctor (not neuro coz too conservative). I heard through the grapevine that there are some people who let their fumarate made in a pharmacy because fumarate is not patented. So basically you should get it in GB as well - ask your doc/pharmacist. When I lived in GB the docs (no MS then) were always very cooperative and gave me the meds I requested, try it out. Good luck.

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  9. James Bingley Thomas
    If you are a regular visitor, you will be aware that Vasilis Vasilopoulos has made it his mission to belittle pretty much everything that we do and indeed the vast majority of the accepted wisdom in the MS field.
    Now you may choose to trust what VV has to say but in our opinion most of what he has to say doesn't square with the evidence.

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  10. "your question is how is progression possible without relapses"

    Nothing of the sort I know that you can have progression without relapse

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  11. "This could be a complementary explanation."

    Could be other things too :-)

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  12. Thank you too, Mr Thomas.

    "accepted wisdom in the MS field"
    In page 21 of the DEFINE study protocol the writers try to support the rationale of testing BG12 by saying that: "...there is evidence that autoimmunity to myelin
    constituents plays a central role in the development of the MS lesion." They support their claims with literature from 1976 to 1995. Thus, they fail to incorporate anything from the last 17 years of MS research, most prominent of which the observation that IN ALL EARLY MS LESIONS THERE ARE NO IMMUNE SYSTEM INFILTRATES. So much for the wisdom.

    "what he has to say doesn't square with the evidence."
    Since MD has made it clear that Prof GG will not bother reading the 2007 study of the beneficial effect of aspirin in the elimination of migraines in children with nutcracker syndrome, maybe you 'll read it and see that what i say is not some personal opinion, and DO square with the evidence.

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  13. I think we can go onto caps lock

    MICROGLIA ARE PART OF THE IMMUNE SYSTEM and I think you will FIND THEM IN ALL EARLY LESIONS.

    http://multiple-sclerosis-research.blogspot.co.uk/2012/04/charcot-tapestry.html

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  14. The references stated by the protocol name CD4+, CD8+, macrophages and microglia. Microglia reside in the brain, they do not infiltrate. The others come from the blood, they infiltrate through BBB. The strangest thing is that while microglia are the only immune representative in the early lesion (and they are there because something else caused CNS damage), MS drugs like Gilenya, Tysabri, Lemtrada, are designed against the blood borne immune agents. Now this is sticking to the evidence!

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  15. Microglia come from the blood! They don't grow in the brain!

    Chapter 12. The Origin of Microglia and the Development of the Brain. Flavia R. S. Lima, Anna Carolina C. da Fonseca, Giselle P. Faria, Luiz Gustavo F. Dubois, ...

    Abstract
    We discuss the origin and development of microglial cells and their influence on neural development. Unlike astrocytes, oligodendrocytes, and neurons, which are derived from neuroectoderm, microglial cells originate from mesoderm. Microglial hematopoietic precursors enter the developing CNS from the bloodstream, ventricles, and meninges. In the brain, these cells migrate and proliferate, as ameboid microglia, and become distributed throughout the nervous parenchyma. Ameboid microglial cells differentiate into ramified microglia when they reach their definitive location. The factors that control the invasion of the nervous parenchyma, migration, proliferation, and differentiation of microglial cells are not completely known. These important events may depend on environmental factors such as soluble or cell-surface-bound molecules and components of the extracellular matrix. In the developing CNS, microglial cells are involved in clearing cell debris and withdrawing transitory or misdirected axons, and presumably support neurogenesis, cell survival, and neurite growth. In the adult brain, activated microglia occur mostly in response to neuronal injuries, when, they destroy invading microorganisms, remove harmful debris, and promote tissue repair, as well as partaking in the immune response by secreting cytokines, facilitating the return to homeostasis. Microglial activation is an important event in the defense of the nervous parenchyma against infectious, neurodegenerative, and inflammatory diseases. The majority of data in the literature describes microglial cells in a neuropathological context. Little is known of the development of these cells in the nervous parenchyma and their effective role in neurogenesis.

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  16. I agree that cells that become microglia come from the blood, but they have a very slow turnover rate, hence the comment about them being resident cells of the brain partly both right

    If you want to quote sentences from papers at me...we can all read...and whilst people writing the papers may talk about T cells and macrophages and myelin basic protein autoimmunity.... so what. This may not have anything to do with what I think is going on or what the paper is actually showing.
    This is why you have to interpret papers no believe everything you read.

    Always be careful about saying there are no other cells near because protein factors can travel and so other cells do not need to be nearby. For example many lesions have antibodies in them but a B cell does not need to be anywhere near. Likewise how many lymphocytes would you need to trigger a lesion...probably not many.

    You can have microglial aggregates without T cells and could still have T cells causing the problem.

    It looks like there are too many (early lesions) microglial aggregates for them all to form MS lesions, some probably resolve..

    Finally If I was sticking to evidence.....I would think that the action of Gilenya was mainly in lymph glands and not the blood as a mechanism of action but I would also know that it accumulates in nervous tissue and their are targets for the drug in brain and on the blood vessels.

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  17. I put more interest in looking at
    responses to therapy into ideas of what is going on, that listening to dogma. Dogma does not treat anything..treatments do.

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  18. The EU commission banned Dimethylfumarate from products in 2009

    http://www.bis.gov.uk/assets/biscore/consumer-issues/docs/d/12-664-dimethylfumarate-direction-2012-dmf-guidance.pdf

    So this raises 3 questions for me

    1. If Dimethylfumarate is as toxic as the EU commission says, why can it be used in drugs?

    2. If Dimethylfumarate is used in drugs isn't it as toxic as they want to make us believe?

    3. Is this ban going to have an impact on the pricing of BG12? Because if you ban a product the production lines will be shut down and the supply will be much lower.

    I find it very interesting that the ban was spoken in the Phase 1 clinical trial of BG12. But that could be a coincidence, couldn't it?

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  19. Not had chance to read all above, but does this fit in anywhere ?
    http://jnnp.bmj.com/content/83/3/e1.154.abstract

    Regards

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    1. Looks promising but only 17 patients. A bigger trial needs to be done before any definitive conclusions can be drawn. Looks like things might finally be moving for PPMS though at long last. Also nice to see translation from animal models to humans, another one in the eye for the naysayers who think all animal research is useless.

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    2. Amiloride is Alasdair Cole's 'best bet' out of all the current neuroprotective potential candidates (Alasdair is one of the key developers of Alemtuzumab for MS). I'd rate his opinion pretty highly...

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